Relative contribution of pharmacokinetics and immune signatures to clinical outcomes in patients with HIV-associated cryptococcal meningitis

Katharine E. Stott; Dumizulu Tembo; Cheusisime Kajanga; Ajisa Ahmadu; Dumisan Namakhwa; Ruwanthi Kolamunnage-Dona; Chandni Sarker; Melanie Moyo; Ebbie Gondwe; Wezi Chimang’anga; Madalitso Chasweka; Reya V. Shah; David S. Lawrence; Thomas S. Harrison; Joseph N. Jarvis; David Lalloo; William Hope; Henry Mwandumba; T. Chimphambano; E. Dziwani; A. Kadzilimbile; S. Kateta; E. Kossam; C. Kukacha; B. Lipenga; J. Ndaferankhande; M. Ndalama; R. Shah; A. Singini; A. Zambasa; J. Goodall; K. Lechiile; N. Mawoko; T. Mbangiwa; J. Milburn; R. Mmipi; C. Muthoga; P. Ponatshego; I. Rulaganyang; K. Seatla; N. Tlhako; K. Tsholo; S. April; A. Bekiswa; L. Boloko; H. Bookholane; T. Crede; L. Davids; R. Goliath; Moses Kumwenda

doi:10.1093/ofid/ofaf190

Relative contribution of pharmacokinetics and immune signatures to clinical outcomes in patients with HIV-associated cryptococcal meningitis

Katharine E. Stott, Dumizulu Tembo, Cheusisime Kajanga, Ajisa Ahmadu, Dumisan Namakhwa, Ruwanthi Kolamunnage-Dona, Chandni Sarker, Melanie Moyo, Ebbie Gondwe, Wezi Chimang’anga, Madalitso Chasweka, Reya V. Shah, David S. Lawrence, Thomas S. Harrison, Joseph N. Jarvis, David Lalloo, William Hope, Henry Mwandumba, T. Chimphambano, E. DziwaniA. Kadzilimbile, S. Kateta, E. Kossam, C. Kukacha, B. Lipenga, J. Ndaferankhande, M. Ndalama, R. Shah, A. Singini, A. Zambasa, J. Goodall, K. Lechiile, N. Mawoko, T. Mbangiwa, J. Milburn, R. Mmipi, C. Muthoga, P. Ponatshego, I. Rulaganyang, K. Seatla, N. Tlhako, K. Tsholo, S. April, A. Bekiswa, L. Boloko, H. Bookholane, T. Crede, L. Davids, R. Goliath, Moses Kumwenda

Research output: Contribution to journal › Article › peer-review

Abstract

Background

Host immune responses to HIV-associated cryptococcal meningitis are critical in disease outcome. Their interaction with antifungal drug exposure is poorly understood. This study explored associations between immune biomarkers, antifungal drug exposure, and clinical outcomes in HIV-associated cryptococcal meningitis.

Methods

We analyzed serial plasma and cerebrospinal fluid immune biomarkers from 64 participants recruited from the AMBITION-cm trial. We estimated individual-level exposure to amphotericin B, flucytosine, and fluconazole. Associations between immune biomarkers, pharmacokinetic parameters, and clinical outcomes were evaluated.

Results

An inflammatory cerebrospinal fluid response, characterized by coordination between tumor necrosis factor-α, granulocyte colony-stimulating factor, and interleukin-7 signaling, was linked to low fungal burden, low intracranial pressure, and survival. However, the value of specific immune biomarkers did not predict EFA or mortality. Exposure to amphotericin B was significantly associated with EFA.

Conclusions

Favorable clinical outcomes from HIV-associated cryptococcal meningitis are associated with coordinated inflammatory and cytotoxic responses in the central nervous system. Antifungal drug exposure was the dominant predictor of EFA.

Original language	English
Article number	ofaf190
Pages (from-to)	ofaf190
Journal	Open Forum Infectious Diseases
Volume	12
Issue number	4
Early online date	2 Apr 2025
DOIs	https://doi.org/10.1093/ofid/ofaf190
Publication status	Published - 2 Apr 2025

Keywords

amphotericin B
cryptococcal meningitis
immunomodulation
pharmacodynamics
pharmacokinetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Stott, K. E., Tembo, D., Kajanga, C., Ahmadu, A., Namakhwa, D., Kolamunnage-Dona, R., Sarker, C., Moyo, M., Gondwe, E., Chimang’anga, W., Chasweka, M., Shah, R. V., Lawrence, D. S., Harrison, T. S., Jarvis, J. N., Lalloo, D., Hope, W., Mwandumba, H., Chimphambano, T., ... Kumwenda, M. (2025). Relative contribution of pharmacokinetics and immune signatures to clinical outcomes in patients with HIV-associated cryptococcal meningitis. Open Forum Infectious Diseases, 12(4), ofaf190. Article ofaf190. https://doi.org/10.1093/ofid/ofaf190

@article{cc1bc57b6f5e4aaf9e9710a6c066dbf4,

title = "Relative contribution of pharmacokinetics and immune signatures to clinical outcomes in patients with HIV-associated cryptococcal meningitis",

abstract = "BackgroundHost immune responses to HIV-associated cryptococcal meningitis are critical in disease outcome. Their interaction with antifungal drug exposure is poorly understood. This study explored associations between immune biomarkers, antifungal drug exposure, and clinical outcomes in HIV-associated cryptococcal meningitis.MethodsWe analyzed serial plasma and cerebrospinal fluid immune biomarkers from 64 participants recruited from the AMBITION-cm trial. We estimated individual-level exposure to amphotericin B, flucytosine, and fluconazole. Associations between immune biomarkers, pharmacokinetic parameters, and clinical outcomes were evaluated.ResultsAn inflammatory cerebrospinal fluid response, characterized by coordination between tumor necrosis factor-α, granulocyte colony-stimulating factor, and interleukin-7 signaling, was linked to low fungal burden, low intracranial pressure, and survival. However, the value of specific immune biomarkers did not predict EFA or mortality. Exposure to amphotericin B was significantly associated with EFA.ConclusionsFavorable clinical outcomes from HIV-associated cryptococcal meningitis are associated with coordinated inflammatory and cytotoxic responses in the central nervous system. Antifungal drug exposure was the dominant predictor of EFA.",

keywords = "amphotericin B, cryptococcal meningitis, immunomodulation, pharmacodynamics, pharmacokinetics",

author = "Stott, \{Katharine E.\} and Dumizulu Tembo and Cheusisime Kajanga and Ajisa Ahmadu and Dumisan Namakhwa and Ruwanthi Kolamunnage-Dona and Chandni Sarker and Melanie Moyo and Ebbie Gondwe and Wezi Chimang{\textquoteright}anga and Madalitso Chasweka and Shah, \{Reya V.\} and Lawrence, \{David S.\} and Harrison, \{Thomas S.\} and Jarvis, \{Joseph N.\} and David Lalloo and William Hope and Henry Mwandumba and T. Chimphambano and E. Dziwani and A. Kadzilimbile and S. Kateta and E. Kossam and C. Kukacha and B. Lipenga and J. Ndaferankhande and M. Ndalama and R. Shah and A. Singini and A. Zambasa and J. Goodall and K. Lechiile and N. Mawoko and T. Mbangiwa and J. Milburn and R. Mmipi and C. Muthoga and P. Ponatshego and I. Rulaganyang and K. Seatla and N. Tlhako and K. Tsholo and S. April and A. Bekiswa and L. Boloko and H. Bookholane and T. Crede and L. Davids and R. Goliath and Moses Kumwenda",

year = "2025",

month = apr,

day = "2",

doi = "10.1093/ofid/ofaf190",

language = "English",

volume = "12",

pages = "ofaf190",

journal = "Open Forum Infectious Diseases",

issn = "2328-8957",

publisher = "Oxford University Press",

number = "4",

}

Stott, KE, Tembo, D, Kajanga, C, Ahmadu, A, Namakhwa, D, Kolamunnage-Dona, R, Sarker, C, Moyo, M, Gondwe, E, Chimang’anga, W, Chasweka, M, Shah, RV, Lawrence, DS, Harrison, TS, Jarvis, JN, Lalloo, D, Hope, W, Mwandumba, H, Chimphambano, T, Dziwani, E, Kadzilimbile, A, Kateta, S, Kossam, E, Kukacha, C, Lipenga, B, Ndaferankhande, J, Ndalama, M, Shah, R, Singini, A, Zambasa, A, Goodall, J, Lechiile, K, Mawoko, N, Mbangiwa, T, Milburn, J, Mmipi, R, Muthoga, C, Ponatshego, P, Rulaganyang, I, Seatla, K, Tlhako, N, Tsholo, K, April, S, Bekiswa, A, Boloko, L, Bookholane, H, Crede, T, Davids, L, Goliath, R & Kumwenda, M 2025, 'Relative contribution of pharmacokinetics and immune signatures to clinical outcomes in patients with HIV-associated cryptococcal meningitis', Open Forum Infectious Diseases, vol. 12, no. 4, ofaf190, pp. ofaf190. https://doi.org/10.1093/ofid/ofaf190

TY - JOUR

T1 - Relative contribution of pharmacokinetics and immune signatures to clinical outcomes in patients with HIV-associated cryptococcal meningitis

AU - Stott, Katharine E.

AU - Tembo, Dumizulu

AU - Kajanga, Cheusisime

AU - Ahmadu, Ajisa

AU - Namakhwa, Dumisan

AU - Kolamunnage-Dona, Ruwanthi

AU - Sarker, Chandni

AU - Moyo, Melanie

AU - Gondwe, Ebbie

AU - Chimang’anga, Wezi

AU - Chasweka, Madalitso

AU - Shah, Reya V.

AU - Lawrence, David S.

AU - Harrison, Thomas S.

AU - Jarvis, Joseph N.

AU - Lalloo, David

AU - Hope, William

AU - Mwandumba, Henry

AU - Chimphambano, T.

AU - Dziwani, E.

AU - Kadzilimbile, A.

AU - Kateta, S.

AU - Kossam, E.

AU - Kukacha, C.

AU - Lipenga, B.

AU - Ndaferankhande, J.

AU - Ndalama, M.

AU - Shah, R.

AU - Singini, A.

AU - Zambasa, A.

AU - Goodall, J.

AU - Lechiile, K.

AU - Mawoko, N.

AU - Mbangiwa, T.

AU - Milburn, J.

AU - Mmipi, R.

AU - Muthoga, C.

AU - Ponatshego, P.

AU - Rulaganyang, I.

AU - Seatla, K.

AU - Tlhako, N.

AU - Tsholo, K.

AU - April, S.

AU - Bekiswa, A.

AU - Boloko, L.

AU - Bookholane, H.

AU - Crede, T.

AU - Davids, L.

AU - Goliath, R.

AU - Kumwenda, Moses

PY - 2025/4/2

Y1 - 2025/4/2

N2 - BackgroundHost immune responses to HIV-associated cryptococcal meningitis are critical in disease outcome. Their interaction with antifungal drug exposure is poorly understood. This study explored associations between immune biomarkers, antifungal drug exposure, and clinical outcomes in HIV-associated cryptococcal meningitis.MethodsWe analyzed serial plasma and cerebrospinal fluid immune biomarkers from 64 participants recruited from the AMBITION-cm trial. We estimated individual-level exposure to amphotericin B, flucytosine, and fluconazole. Associations between immune biomarkers, pharmacokinetic parameters, and clinical outcomes were evaluated.ResultsAn inflammatory cerebrospinal fluid response, characterized by coordination between tumor necrosis factor-α, granulocyte colony-stimulating factor, and interleukin-7 signaling, was linked to low fungal burden, low intracranial pressure, and survival. However, the value of specific immune biomarkers did not predict EFA or mortality. Exposure to amphotericin B was significantly associated with EFA.ConclusionsFavorable clinical outcomes from HIV-associated cryptococcal meningitis are associated with coordinated inflammatory and cytotoxic responses in the central nervous system. Antifungal drug exposure was the dominant predictor of EFA.

AB - BackgroundHost immune responses to HIV-associated cryptococcal meningitis are critical in disease outcome. Their interaction with antifungal drug exposure is poorly understood. This study explored associations between immune biomarkers, antifungal drug exposure, and clinical outcomes in HIV-associated cryptococcal meningitis.MethodsWe analyzed serial plasma and cerebrospinal fluid immune biomarkers from 64 participants recruited from the AMBITION-cm trial. We estimated individual-level exposure to amphotericin B, flucytosine, and fluconazole. Associations between immune biomarkers, pharmacokinetic parameters, and clinical outcomes were evaluated.ResultsAn inflammatory cerebrospinal fluid response, characterized by coordination between tumor necrosis factor-α, granulocyte colony-stimulating factor, and interleukin-7 signaling, was linked to low fungal burden, low intracranial pressure, and survival. However, the value of specific immune biomarkers did not predict EFA or mortality. Exposure to amphotericin B was significantly associated with EFA.ConclusionsFavorable clinical outcomes from HIV-associated cryptococcal meningitis are associated with coordinated inflammatory and cytotoxic responses in the central nervous system. Antifungal drug exposure was the dominant predictor of EFA.

KW - amphotericin B

KW - cryptococcal meningitis

KW - immunomodulation

KW - pharmacodynamics

KW - pharmacokinetics

U2 - 10.1093/ofid/ofaf190

DO - 10.1093/ofid/ofaf190

M3 - Article

SN - 2328-8957

VL - 12

SP - ofaf190

JO - Open Forum Infectious Diseases

JF - Open Forum Infectious Diseases

IS - 4

M1 - ofaf190

ER -

Relative contribution of pharmacokinetics and immune signatures to clinical outcomes in patients with HIV-associated cryptococcal meningitis

Abstract

Keywords

UN SDGs

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